China COVID vaccine – Accestra Consulting

2020 China Drug Evaluation Report – Part 4

Accestra — Fri, 28 Jan 2022 03:49:26 +0000

Drug review and approval challenges in 2020 included overcoming difficulties in completing facility inspection, conducting remote advisory meetings, and facilitating communications through a variety of tools to help advance drug development and accelerate approval.

As a follow-up on part 3 of the Drug Evaluation Report 2020, part 4 gives an overview of on-site/distant GMP/GCP/GLP inspection, advisory meetings, and technical issue communication pathways, including phone calls, e-mails, and e-platform services by CDE..

1. Drug GMP Inspection

To assess the compliance of a site with the GMP/GCP/GLP of China, the Center of Drug Evaluation (CDE) requests the Center for Food and Drug Inspection (CFDI) for facility inspection when information, such as high-risk products, quality complaints, adverse events or data from an application dossier or other sources, indicate that potential problems or risks exist with a drug product (“For-cause” Inspection). For any application (NDA or ANDA) submitted after July 1st, 2020, a notice of on-site inspection is issued by CDE within 40 workdays after application acceptance if a “cause” warrants a timely investigation of that product. The notice and any other Information to guide the preparation for on-site inspection can be found on the e-platform of CDE through the “Gateway for Applicant”.

1.1 On-site Inspection

In 2020, CDE requested 1,235 on-site inspections, including 792 GMP inspections, 439 GCP inspections, and 4 GLP inspections. Including the backlog of previous year, 818 on-site inspections were completed by CFDI, correspondingly, 449 GMP reports, 363 GCP reports and 6 GLP reports were submitted to CDE.

1.2 Distant Inspection

Under the international impact of COVID-19 pandemic, overseas on-site inspections were not conducted for a number of reasons such as travel restrictions or risk to health. In these circumstances, distant inspections can represent a suitable means of determining GMP/GCP/GLP compliance based on documents and interviews while supported by IT technologies. In November 2020, CFDI conducted distant inspections for two drug products produced outside of China, the outcome of which was basically in line with the principles of on-site inspection. Nevertheless, on-site inspections should still be conducted once circumstances permit.

2. CDE Advisory Meetings and Communications

Advisory meetings and communications are activities of discussing crucial scientific, technical, and policy issues which are not specified in the guidelines for drug development and review of drug registration. They can be proposed by the applicant of drug registration or requested by CDE if clarifications are required during application review. To provide better guidance on these activities, CDE revised and NMPA issued the Provisions for Communications about Drug Development and Technical Review (NMPA [2020] Decree No.48) in 2020. To expedite drug review and approval, CDE took the initiative and newly established e-platform communication services for technical Q&As both before and after a deficiency notification letter is issued for a drug.

2.1 Overview

In the new model of communication, 3,229 applications were received in 2020 for advisory meetings with an increase of 22.6% comparing to 2019 and among which 2,451 applications were approved. On the e-platform of CDE, 20,285 questions were received about general technical issues in 2020 with an increase of 22.4%. In addition, more than ten thousand of phone calls and e-mails were received and answered. To compare the number of advisory meetings and communications between the last years, please see the diagrams below (Fig. 1 and 2).

Fig. 1 Number of Applications for Advisory Meetings from 2016 to 2020

Fig. 2 Number of General Technical Issue Q&As from 2017 to 2020: the e-platform of general technical issue Q&As has been in operation since 2017.

2.2 CDE Advisory Meetings

To improve the efficiency with which expert advice on crucial issues is obtained, CDE determines whether a formal conference is required for a drug or quick answers can be given in writing after receiving the application. If a formal conference is confirmed, it can be held as a teleconference, videoconference, or face-to-face (F2F) meeting. Among 2,451 applications approved for advisory meetings in 2020, 268 conferences were held, and the rest were replied in writing. Classify these meetings according to their topics, Class II meetings shared 76.42% of total approvals, among which pre-IND meetings were the most requested (37.49%). To learn the classification of advisory meetings, please see the overview of advisory meetings below for 2020 (Table 1).

Table 1. Overview of CDE Advisory Meeting Applications and Approvals in 2020

Classification of CDE Advisory Meetings		Number of Applications	%	Number of Approvals	%
Class I (Meetings for crucial safety issues in clinical trials or major technical issues in drug development of breakthrough therapies)		202	6.26%	138	5.63%
Class II	Pre-IND Meeting	1,250	38.71%	919	37.49%
	IND Meeting	228	7.06%	171	6.98%
	End of Phase I Trial Meeting	231	7.15%	213	8.69%
	End of Phase II Trial Meeting	241	7.46%	188	7.67%
	Pre-NDA Meeting	417	12.91%	324	13.22%
	NDA Meeting	71	2.20%	45	1.84%
	Generic Consistency Evaluation Meeting	1	0.03%	3	0.12%
	Complex Generic ANDA Meeting	17	0.53%	10	0.41%
Class III (Other meetings)		571	17.68%	440	17.95%
In Total		3,229	100%	2,451	100%

Note: Some of the advisory meetings approved in 2020 were backlog of the previous year.

2.3 Fast-track Review Meetings

Under the COVID-19 public health emergency, CDE approved many new drug therapies in 2020 for patients suffering from the pandemic through fast-track review pathways. To shorten the timeline for approval, CDE encouraged drug innovators to file applications while development and study of drugs were ongoing. Within 24 hours after an application is received, CDE communicated with the applicant proactively about any crucial scientific matters and the feasibility of approval. For any new technological challenges, CDE invited independent experts for advisory meetings and consultations to obtain advice and discuss solutions. The decisions made on these approvals were further included in the technical guidelines to support drug development and speed new therapies to market.

2.4 Technical Issue Communications

Except for the advisory meetings, applicants of drug registration can also ask questions about general technical issues on the e-platform of CDE. Classify the questions received according to their topics, issues about application acceptance and Active Pharmaceutical Ingredient (API)/Excipient/Packaging were the most asked. Classify the questions received according to drug categories, issues about chemical drugs were the most asked. For more details, please see the overview of general technical issue Q&As below for 2020 (Table 2).

Table 2. Number of Q&As for General Technical Issues in 2020

CLASSIFICATION OF Q&As	API/ EXCIPIENT / PACKING	CHEMICAL DRUG	BIOLOGICAL PRODUCT	TRADITIONAL CHINESE MEDICINE & NATURAL MEDICINE	OTHERS	IN TOTAL
Application Acceptance	315	2,396	790	141	397	4,39
API/ Excipient / Packing	2,764	1,055	85	30	18	3,952
Techical Review – CMC	47	1,077	482	46	18	1,670
Genric Consistency Evaluation	10	1,258	7	2	35	1,312
Technical Review – Clinical Trials	0	824	335	59	37	1,255
Technical Review – Regulatory Compliance	47	668	216	64	47	1,042
Material Supplements for Deficiency Letter	163	718	87	28	14	1,010
Guidelines	33	519	164	58	118	892
CDE e-Platform	225	151	29	4	52	461
Technical Review – Pharmacology, Toxicology	0	158	113	16	3	290
Technical Review – Statistics / Clinical Pharmacology	0	111	34	4	3	152
Others	197	2,331	607	175	381	3,691
In Total	3,804	11,338	3,381	636	1,125	20,285

Accestra Consulting Provides China Regulatory Affairs Outsourcing for:

Drugs/Pharmaceutical,
Food and Feed products for China NMPA (Formerly CFDA).
Regulatory approval including product registration for China Investigational New Drug (IND),
China New Drug Application (NDA),
China Drug Master File (DMF) for APIs,
Excipients and Packaging Materials,
ANDA,
eCTD submission and others.

Read part 1 of the 2020 Drug Evaluation Report.

Read part 2 of the 2020 Drug Evaluation Report.

Contact Accestra Consulting Group

2020 China Drug Evaluation Report – Part 3

Samantha Beneke — Sat, 14 Aug 2021 01:11:28 +0000

Part 3. Administrative Approval and Fast Track Review Pathways

Administrative approval.
Fast track review pathways.
2.1. Specialized pathway.
2.2. Breakthrough therapy.
2.3. Conditional approval.
2.4. Priority Review.

In 2020 CDE approved:

1,435 Investigational New Drug (IND) applications,
208 New Drug Applications (NDAs),
918 Abbreviated New Drug Applications (ANDAs).

This includes 59 drugs for the treatment of COVID-19.

As a follow-up on part 2 of the Drug Evaluation Report 2020, part 3 gives an overview of administrative drug approvals and fast track review pathways by CDE.

This includes specialized pathways, breakthrough therapy, conditional approval, and priority review.

1. Administrative Approval

CDE administratively approves a drug application regardless of whether it needs a technical review.

In 2020, there was a total of 8,646 approved applications, an increase of 44.51% year on year.

Most of these applications (5,647) were reviewed technically before approval, such as:

Clinical Trial Applications (CTAs),
New Drug Applications (NDAs),
Abbreviated New Drug Applications (ANDAs),
License renewal of imported drugs.

Other applications (2,972) were approved without technical reviews, such as temporary drug import applications.

Table 1 below gives an overview of applications administratively approved in 2020.

APPLICATION TYPE		NUMBER OF APPROVALS
		CHEMICAL DRUGS	BIOLOGICAL PRODUCTS	TRADITIONAL CHINESE MEDICINE	IN TOTAL
Approval after technical review	CTAs (incl. confirmatory clinical trials)	1,085	564	37	1,686
	Consistency Evaluations	623	0	0	623
	Supplementary Applications	1,955	615	290	2,860
	License Renewal of Imported Drugs	406	49	23	478
	Re-Review	17	3	7	27
Approval without technical review	Directly Approved Supplementary Applications	2,048	348	141	2,537
	Temporary Import Application	363	60	12	435
IN TOTAL		6,497	1,639	510	8,646

Comparing to 2019, 39.24% more applications were approved after technical review and 55.77% more applications were approved directly (without technical review).

View the diagram below for a comparison between the last three years (Fig. 1).

Fig. 1 Number of Administrative Approvals from 2018 to 2020.

2. Fast Track Review Pathways

CDE used several regulatory pathways to enhance efficiency as well as expedite drug development and approval in 2020.

According to the Provisions for Drug Registration (State Administration for Market Regulation [2020] Decree No. 27), the fast track review pathways are:

Specialized pathway,
Breakthrough therapy,
Conditional approval,
Priority review.

These pathways use a range of approaches, including:

More interactions between CDE reviewers and drug developers,
Greater application process flexibility,
Shortened timelines for review and approval.

During the COVID-19 pandemic, fast track review pathways advanced patient treatments in approving drugs for unmet clinical needs and significant improvements on medical care. This better protected the health of the Chinese public.

Specialized Pathway

A drug reviewed by the Specialized Pathway is used for the treatment or prevention of pandemic disease as part of a declared public health emergency.

The drug review is expedited with:

Increased flexibility:
Accelerated application acceptance,
Parallel proceeding of review,
On-site inspection/audit,
Product testing.

The drug can only be used in a specified period and is based on its medical need for controlling that pandemic disease.

During the COVID-19 pandemic, CDE reviewed 59 chemical drugs, biological products, and traditional Chinese medicines by the specialized pathway in 2020.

Among these:

1 novel drug (i.e., COVID-19 Vaccine (Vero Cell) Inactivated) was approved under controlled conditions,
53 novel drugs were approved for clinical trials,
5 listed drugs were approved to include a new indication of treating coronavirus.

2.2.Breakthrough Therapy

Breakthrough Therapy is a drug for a serious or life-threatening disease for which there is an unmet clinical need or for which there is preliminary clinical evidence demonstrating that the drug may have a substantial clinical improvement over other available therapies.

An application can be submitted to CDE in Phase I or II clinical trial for a drug to be designated as a Breakthrough Therapy.

Once accepted, a breakthrough therapy designation will have the following features:

Priority of advisory communication and meetings with CDE as well as more intensive CDE guidance on drug development.
Priority review with shortened approval timeline.
Priority of on-site inspection/audit and product testing.

In 2020, CDE designated 24 of the 147 applied drugs (16%) as breakthrough therapies.

2.3. Conditional Approval

A drug receives Conditional Approval if there is an urgent medical need for the drug to treat a serious, life-threatening, or public health emergency disease.

The drug can result in having surrogate endpoints, intermediate endpoints, or early clinical data as to efficacy measures.

If the clinical study demonstrates that the benefit of the drug overweighs its risk, it will be approved under controlled conditions.

In 2020, 15 novel drugs received conditional approvals from CDE and provided new therapies for:

COVID-19 pandemic,
Non-small cell lung cancer,
Ovarian cancer and more.

2.4. Priority Review

A drug receives a Priority Review if CDE determines that the drug could potentially provide significant advances in medical care or serve previously unmet medical needs.

The drug is reviewed in an expedited timeline, within 130 workdays instead of the standard 200 workdays, and within 70 workdays for a drug already approved overseas to treat a rare or “orphan” disease.

219 drugs were designated Priority Review by CDE in 2020, among which 42 drugs were pediatric and rare disease drugs.

Including the backlog of priority reviews of the previous year, 217 drugs (of 121 categories) were approved in 2020, an increase of 51.7% compared to 2019.

The highlight examples were:

Almonertinib mesylate tablets,
Agalsidase,
Concentrated injection,
Mulberry twig alkaloids tablets.

Table 2 gives an overview of priority review and approval in 2020 and compares the number of approvals from 2016 to 2020.

REGISTRATION APPLICATION	2016		2017		2018		2019		2020
	NUMBER OF CATEGORIES	RATIO	NUMBER OF CATEGORIES	RATIO	NUMBER OF CATEGORIES	RATIO	NUMBER OF CATEGORIES	RATIO	NUMBER OF CATEGORIES	RATIO
Novel Drug with substantial clinical advance	0	14.30%	33	66%	39	47%	40	48.80%	36	29.80%
Parallel application	0	0%	4	8%	14	16.90%	7	8.50%	30	24.80%
AIDS Drug	0	0%	0	0%	0	0%	0	0%	3	2.50%
Orphan designation for rare disease	0	0%	0	0%	3	3.60%	6	7.30%	11	9.10%
Pediatric drug	4	57.10%	1	2%	9	10.80%	7	8.50%	8	6.60%
Re-application after generic consistency evaluation	0	0%	0	0%	5	6%	8	9.80%	20	16.50%
Major national R&D program drug	0	0%	0	0%	0	0%	5	6.10%	9	7.40%
Generic of coming off-patient drug	1	14%	2	4%	4	4.80%	7	8.50%	4	3.30%
Drug of urgent clinical need or of market shortage	0	0%	2	4%	3	3.60%	0	0%	0	0.00%
First generic drug approval	1	14.30%	8	16%	6	7.20%	2	2.40%	0	0.00%
IN TOTAL	7	100%	50	100%	83	100%	82	100%	121	100%